DESCRIPTION: Applicant's Abstract The abuse of opioid drugs exerts a dramatic cost on our society. Chronic use of opioid drugs results in drug dependence as characterized by a withdrawal syndrome upon drug removal. Drug dependence and withdrawal are likely to be mediated in part by neurochemical changes in the brain, such as the upregulation of cAMP signaling pathways. Previous work has shown that chronic morphine treatment can increase the ability of the cAMP system to potentiate GABAergic synaptic transmission in the nucleus accumbens, and that agonists at opioid receptors can normalize this altered response to cAMP signaling. However, the neurochemical mechanisms mediating this response to chronic morphine have not been identified. The goal of this proposal is to investigate the cellular mechanisms that mediate chronic morphine-induced changes in synaptic transmission in the nucleus accumbens. Whole-cell voltage-clamp recordings will be made from interneurons in nucleus accumbens slices under visual control, and the mechanisms by which chronic morphine alters GABAergic inhibitory postsynaptic currents (IPSCs) will be identified. This will involve, determining the point(s) in the cAMP signaling cascade that are altered by chronic morphine, characterizing the inhibitory feedback of this system by adenosine, and determining how acute opioid exposure normalizes synaptic transmission. These studies will enhance our understanding of the neurochemical changes that contribute to drug dependence and withdrawal, and may aid the development of new therapies for the treatment of addiction.